Lung tissue viscoelasticity is preserved with bleomycin-induced fibrosis in mice

In pulmonary fibrosis, excessive scar tissue accumulates in the alveolar interstitial space, impairing gas exchange and compromising lung function. This fibrotic remodeling results in tissue stiffening, but more complex lung mechanical properties critical to tissue function, such as viscoelasticity and stress relaxation, remain poorly defined. To address this gap, we use the bleomycin aged mouse model to characterize both bulk and spatially-resolved viscoelastic mechanical properties of normal and fibrotic lungs. Our analysis reveals that while bleomycin-induced fibrosis leads to heterogeneously increased lung stiffness, viscoelasticity as measured by tan delta (ratio of loss to storage modulus) and stress relaxation timescales remains remarkably consistent as a function of both age and bleomycin treatment. This unexpected preservation of viscoelasticity despite fibrotic stiffening highlights a previously underappreciated mechanical phenotype of fibrotic lungs. To model these distinct mechanical features in vitro, we utilize a hyaluronic acid-based hydrogel system that largely recapitulates the viscoelastic mechanical properties observed in both normal and fibrotic lungs. Human lung fibroblasts seeded on these hydrogels display increased activation on fibrotic lung-mimicking substrates. These findings provide new insight into the mechanical consequences of fibrosis and establish a tunable in vitro hydrogel platform mimicking key tissue viscoelastic properties. STATEMENT OF SIGNIFICANCE: Tissue viscoelasticity plays a pivotal role in diverse biological processes including tumorigenesis, stem cell differentiation, and fibrosis. While pulmonary fibrosis is known to result in tissue stiffening, it is unclear how lung viscoelasticity changes with fibrosis. We comprehensively characterize both normal and fibrotic lung viscoelasticity using a well-established aged mouse model. We make the surprising finding that despite quantifying characteristic heterogeneous changes in tissue stiffness during fibrosis progression, viscoelasticity is remarkably consistent in both normal and fibrotic lung in young and aged mouse models. We then engineer hydrogels that largely recapitulate the viscoelastic properties measured in tissue, setting the stage for future work applying tissue-mimetic hydrogels as cell culture models of fibrosis.